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Molecular basis of MHC I quality control in the peptide loading complex

Author

Listed:
  • Alexander Domnick

    (Goethe University Frankfurt)

  • Christian Winter

    (Goethe University Frankfurt)

  • Lukas Sušac

    (Goethe University Frankfurt)

  • Leon Hennecke

    (Goethe University Frankfurt)

  • Mario Hensen

    (University of Oxford)

  • Nicole Zitzmann

    (University of Oxford)

  • Simon Trowitzsch

    (Goethe University Frankfurt)

  • Christoph Thomas

    (Goethe University Frankfurt)

  • Robert Tampé

    (Goethe University Frankfurt)

Abstract

Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.

Suggested Citation

  • Alexander Domnick & Christian Winter & Lukas Sušac & Leon Hennecke & Mario Hensen & Nicole Zitzmann & Simon Trowitzsch & Christoph Thomas & Robert Tampé, 2022. "Molecular basis of MHC I quality control in the peptide loading complex," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32384-z
    DOI: 10.1038/s41467-022-32384-z
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    References listed on IDEAS

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    1. Huan Lan & Esam T. Abualrous & Jana Sticht & Laura Maria Arroyo Fernandez & Tamina Werk & Christoph Weise & Martin Ballaschk & Peter Schmieder & Bernhard Loll & Christian Freund, 2021. "Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Andreas Blees & Dovile Januliene & Tommy Hofmann & Nicole Koller & Carla Schmidt & Simon Trowitzsch & Arne Moeller & Robert Tampé, 2017. "Structure of the human MHC-I peptide-loading complex," Nature, Nature, vol. 551(7681), pages 525-528, November.
    4. Andrew C. McShan & Christine A. Devlin & Giora I. Morozov & Sarah A. Overall & Danai Moschidi & Neha Akella & Erik Procko & Nikolaos G. Sgourakis, 2021. "TAPBPR promotes antigen loading on MHC-I molecules using a peptide trap," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
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    Cited by:

    1. Lenong Li & Xubiao Peng & Mansoor Batliwala & Marlene Bouvier, 2023. "Crystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Andrew C. McShan & David Flores-Solis & Yi Sun & Samuel E. Garfinkle & Jugmohit S. Toor & Michael C. Young & Nikolaos G. Sgourakis, 2023. "Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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